Phenethylamides

ABSTRACT

Novel chloro- or alkoxy-substituted phenethylamides, optionally substituted on the nitrogen by alkyl and containing an alkyl-, an alkanoyloxyalkyl-, a hydroxyalkyl- or a diphenoxyalkylacylamino group (I) are pharmacologically active as bronchodilators and as central nervous system depressants. Compounds (I) are provided by (a) acylating a substituted phenethylamine (II) with a reactive derivative, e.g., halide or anhydride, of an alkanoic, alkanoyloxyalkanoic, hydroxyalkanoic, or diphenoxyalkanoic acid (III) or (b) dealkanoylating an alkanoyloxy alkyl compound (Ia) to provide the corresponding hydroxyalkyl compound (Ib).

United States Patent McCaully et al.

[ 51 3,689,557 51 Sept. 5, 1972 [54] PHENETHYLAMIDES [72] Inventors: Ronald J. McCaully, Malvern; George L. Conklin, Marvertown, both of Pa.

[73] Assignee: American Home Products Corporation, New York, N.Y.

[22] Filed: June 9, 1969 [2]] Appl. No.: 831,725

[52] US. Cl. ..260/559 B, 260/490, 260/501 l 260/501.2l, 260/562 R, 260/562 A, 424/324 [51] Int. Cl ..C07c 103/38 [58] Field of Search ..260/562, 472, 559

[56] References Cited UNITED STATES PATENTS 3/1970 I-loulihan et a1. ..260/562 OTHER PUBLICATIONS Shapiro et al., .I. Am. Chem. Soc., Vol. 81, p. 6322- 29 (1959).

Moore et al., J. Am. Chem. Soc., Vol. 76, p. 3656- 62 (1954).

Kametan et al., Chemical Abstracts, Vol. 54, Col. 15l7gh (1960).

Bennington, Chem. Abstracts, Vol. 55, C01. 18727- 187280961). Bhattacharya, Chem. Abstracts, Vol. 70, article 28800e (1969).

Spath et al., Monatschafte Chimie, Vol.51, p. 190- 204 (1928).

Nerdel et al., Chemical Abstracts, Vol. 53, C01. 21785 (1959).

Primary Examiner-Henry R. Jiles Assistant Examinerl-larry I. Moatz Attorney-Joseph Martin Weigman [5 7] ABSTRACT 3 Claims, N0 Drawings PHENETHYLAMIDES This invention relates to novel phenethylamide compounds with valuable pharmacological properties. More particularly, it is concerned with chloroor alkoxyphenethylamides, optionally substituted on the nitrogen with alkyl, and containing an alkyl-, an alkanoyloxyalkyl-, a hydroxyalkylor a diphenoxymethylacylamino group. These compounds exhibit bronchodilating activity and central nervous system depressant activity in standard pharmacological tests when administered to warm-blooded laboratory animals.

DESCRIPTION OF THE INVENTION The compounds contemplated by this invention are selected from those of Formula I:

R H I wherein R is chloro and R is hydrogen or R and R are lower)alkoxy; R is hydrogen or (lower)alkyl; and R is (lower)alkyl, lower)alkanoyloxy(lower)alkyl, hydroxy(lower)alkyl or diphenoxymethyl, provided, however, that when R and R are (lower)alkoxy and R is hydroxymethyl or (lower)alkyl, R is other than hydrogen, and non-toxic, acid addition salts thereof.

Special mention is made of a family comprising an especially valuable sub generic aspect of this invention. These are compounds of Formula I wherein: R is chloro and R is hydrogen or R and R are methoxy; R is hydrogen or methyl; and R is methyl, acetoxymethyl, hydroxymethyl or diphenoxymethyl, provided, however, that when R and R are methoxy and R is hydroxymethyl or methyl, R is other than hydrogen.

Also valuable embodiments of this invention are the following:

N-(3,4-dimethoxyphenethyl)-N-methylacetamide, and its hydrochloride;

N-( 3 ,4-dimethoxyphenethyl )-2-hydroxyacetamide;

N-(4-chlorophenethyl)-2-hydroxyacetamide, acetate;

N-( 4-chlorophenethyl)-2-hydroxyacetamide; and

N-(3,4-dimethoxyphenethyl)glyoxylamide, diphenylacetal, i.e., a compound of Formula I wherein R and R are methoxy, R is hydrogen and R is diphenoxymethyl.

With reference to Formula I and the definition of the substituents, (lower)alkoxy contemplates hydrocarbon alkoxy groups, straight chain and branched of from about one to about six carbon atoms, illustrative members of which are methoxy ethoxy, n-propoxy, ipropoxy, n-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy and the like; methoxy is preferred. The term (lower)alkyl contemplates hydrocarbon substituents of from about one to about six carbon atoms, straight chain and branched, illustrative members of which are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, npentyl, 2-methylpentyl, n-hexyl and the like; the methyl group is preferred. The term (lower)alkanoyloxy( lower)alkyl contemplates (lower)alkyl groups, as

defined above, mono-substituted with alkanoyloxy' groups of from about two to about six carbon atoms, illustrative members of which are acetoxy, npropionyloxy, i-propionyloxy, n-butyroyloxy, n-pentanoyloxy, n-hexanoyloxy, and the like; a preferred lower)alkanoyl(lower)alkyl group is the acetoxymethyl group. The term hydroxy(lower)alkyl contemplates (lower)alkyl groups, as above defined, monosubstituted with hydroxy; a preferred group is the hydroxymethyl group.

The compounds of Formula I hereinabove are prepared by a process comprising a. condensing a phenethylamine of FORMULA ll:

wherein R, R and R are as above defined with a reac tive derivative, e.g., halide or anhydride, of an acid of Formula Ill wherein R is as above defined; or

b. dealkanoylating a compound of Formula la 1'0 4B1 Ia. wherein R, R and R are as above defined and R is (lower)al-kanoyloxy( lower)alkyl, until formation of a compound of Formula Ib:

II) wherein R, R and R are as hereinabove defined, is substantially complete.

To carry out the procedure designated step (a), the phenethylamine (II) can be mixed with about an equal weight of sodium bicarbonate about four parts by weight of ice, about four parts by weight of water and about nine parts by weight of methylene chloride. To the vigorously stirred mixture then is added dropwise at least the stoichiometrical amount of the acylating agent, preferably an acyl halide, dissolved in about five parts of methylene chloride (based on phenethylamine). After about 1 hour, the reaction is substantially complete. In one manner of recovering the product the organic layer is separated, washed with dilute acid, dilute base, water; dried and evaporated to leave the product (I) as a residue.

To carry out the procedure, designated step (b), the alkanoate (la) is reacted with an aqueous base preferably at a somewhat elevated temperature, e.g., about C. In one manner of proceeding, a slurry of the alkanoate (la) in about 12 parts of 50 percent aqueous ethanol is heated with about one/fourth part by weight of sodium hydroxide and 1.5 parts by weight of water on a stream bath for about 1.5 hours. The product (Ib) can be recovered in any convenient manner. One way of doing so is to concentrate the reaction mixture to about one-half its volume in a vacuum then to dilute the concentrate with about an equal volume of water. Extraction with ether, followed by washing, drying and evaporating the extract will leave the product of Formula lb as a residue. These procedures and the others disclosed hereinabove will be exemplified in detail hereinafter.

The starting materials of Formulas II and III are readily available or can be obtained by techniques familiar to those skilled in the art.

Illustrative of important starting materials of Formula II are:

3,4-dimethoxyphenethylamine, CA. 43, 1026b;

4-chlorophenethylamine, CA. 43, 7486g; and N- methy1-3,4-dimethoxy phenethylamine, CA. 50, 9316d.

Illustrative of important starting materials of Formula III are:

acetoxyacetyl chloride and diphenoxyacetyl chloride The compounds of Formula I and salts of this invention have demonstrated pharmacological activity. In particular they have been found to exert a depressant action on the central nervous system when tested under standard and accepted pharmacological procedures in animals, such as mice and rats. They are, therefore, deemed to possess utility in experimental and comparative pharmacology and are of value to treat conditions in animals, such as valuable domestic animals, and in laboratory animals, such as mice, rats and the like, responsive to treatment with central nervous system depressant agents, such as the need to induce a calming effect.

The compounds of Formula I of this invention have been found to act as bronchodilators when tested under standard and accepted pharmacological test procedures in animals, e.g., cats and guinea pigs. They are, therefore, deemed to possess utility in experimental and comparative pharmacology and are of value to treat conditions in animals, such as valuable domestic animals, and in laboratory animals, such as mice, rats, guinea pigs, and the like, responsive to treatment with bronchodilating agents, such as the symptoms of asthma and the broncho-restrictive effects of histamine-like compounds.

The compounds of Formula I of this invention may be administered either alone or in combination with other pharmacologicaly active ingredients. Whether singly or in combination, they may be used in the form of solid compositions for oral administration combined, if desired, with extenders or carriers that are relatively non-toxic or inert. They may be put into tablet, capsule or powder form. On the other hand, they may be administered in liquid form as a suspension of solution in a suitable vehicle for parenteral use. As will be illustrated hereinafter, useful pharmacological action as central nervous system depressant agents will be demonstrated if the active ingredient is supplied to mice at dosages of 12.7, 40, 127 and 400 mg./kg. of body weight.

For bronchodilating purposes, in addition to the above means of administration, resort can be had to inhalation of aerosols or of solutions, e.g., 1:100 or 1:200, or of powders, e.g., percent or 25 percent active ingredient. As will be illustrated hereinafter, useful pharmacological action as bronchodilating agents will be demonstrated if the active ingredient is supplied to guinea pigs in dosages of 25 and 50 mg./kg. of body weight.

hydrochlorides,

The term non-toxic, acid addition salts" contemplates pharmacologically acceptable salts of the instant compounds with organic and inorganic acids, illustrative salts being, for example, hydrobromides, sulphates, phosphates, acetates, methanesulfonates, citrates, malates, pamoates, and the like. They are prepared by standard techniques such as by mixing the compounds of Formula I (which are basic) with the appropriate acid in a solvent, such as acetone or isopropanol, and evaporating to leave the salt as a residue, or by other methods to be exemplified herein.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples are given by way of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departing from the scope and spirit thereof.

EXAMPLE 1 N-(3,4-dimethoxyphenethyl)-2-hydroxy acetamide, acetate A chilled vigorously stirred mixture of 18 g. of sodium bicarbonate, g. of ice, 80 ml. of water and 18.1 g. of 3,4-dimethoxy-phenethylamine in ml. of methylene chloride is treated dropwise with a solution of 17 g. of acetoxyacetyl chloride in 80 ml. of methylene chloride. After the addition is complete, the reaction is stirred for one hour. The methylene chloride layer is separated and washed successively with 4 percent hydrochloric acid, 10 percent sodium bicarbonate solution, and water. The methylene chloride solution is dried (MgSO and evaporated to an oil. On long standing the crystals that separate spontaneously from the oil are slurried in ether and filtered. Filtration affords 1 1.57 g. of N-(3,4-dimethoxyphenethy1)-2-hydroxyacetarnide, acetate, m.p. 6265C.

Anal.Calcd.forC l-l NO C,59.78; 116.81; N498. Found: c.5951; H,6.70; N,4.69.

EXAMPLE2 N-(p-Chorophenethyl)-2-hydroxyacetamide, acetate A chilled, stirred mixture of 27 g. of sodium bicarbonate, 40 g. of ice, ml. of water, 200 ml. of methylenechloride and 25 g. of pchlorophenethylamine is treated dropwise with a solution of acetoxyacetylchloride in ml. of methylene chloride. After the addition is complete, the mixture is stirred for one hour. The methylene chloride layer is washed successively with 4 percent hydrochloric acid, 10 percent sodium bicarbonate solution and water and is dried over magnesium sulfate. Evaporation of the solvent on a rotary evaporator affords a white solid. Recrystallization of the solid affords 35 g. of N-(pchlorophenethyl)-2-hydroxyacetamide, acetate, m.p., 99-10 1 C.

Anal. Calcd. for C H CINO C, 56.37; H, 5.52; Ll, 13.86; N, 5.48 Found: C, 56.62, H, S.l 1; Cl, 13.88; N, 5.23

EXAMPLE 3 N-(p-Chlorophenethyl)-2-hydroxy-acetamide A slurry of 15.0 g. of N-( p-chlorophenethyl)-2- hydroxy-acetamide, acetate in 200 ml. of 50 percent aqueous is treated with a solution of 2.6 g. of sodium hydroxide in 25 ml. of water and the mixture is heated for 1.5 hr. on a steambath. The solvent is evaporated in 5 Anal. Calcd for c,,,H,,c|No,; c, 56.21; H, 5.66;

Cl, 16.59; N, 6.55 C, 56.19; H, 5.60; Cl, 16.74; N, 6.37

Found:

EXAMPLE 4 N-(3,4-Dimethoxyphenethyl)glyoxyl-amide, diphenylacetal From the reaction of g. of diphenoxyacetyl chloride with 6.0 g. of 3,4-dimethoxyphenethylamine, under the reaction conditions of Example 1, N-(3,4- dimethoxyphenethyl)glyoxylamide, diphenylacetal (5.6 g., m.p., 9496C.) is prepared. The analytical sample is recrystallized from cyclohexane.

Anal. Calcd. for C H NO C, 70.74, H, 6.18.

FoundzC, 70.72; H, 5.89.

EXAMPLE 5 N-( 3,4-Dimethoxyphenethyl)-N-methylacetamide and Hydrochloride A solution of 60.0 g. of 3,4-dimethoxy-N- methyphenethyl-amine, hydrochloride in 400 ml. of water is made basic with 80 g. of 50 percent sodium hydroxide solution and extracted with five portions of methylene chloride. The extract is dried (MgSO and evaporated to leave a residue of 32.2 g.- of 3,4- dimethoxy-N-methylphenethylamine as an oil. The oil dissolved in 100 ml. of acetic anhydride is heated for one hour on a steam bath. Excess acetic anhydride is removed by evaporation in vacuo and by codistillation with toluene. A solution of the residue in ether is filtered from a small amount of insoluble solid and treated with ethereal hydrogen chloride. The sticky hydrochloride that separates is repeatedly suspended in fresh ether for conversion to a clean crystalline solid. The product is recrystallized to constant mp from 200 ml. of hot diethyl ketone to give g. of N-(3,4-

dimethoxyphenethyl)-N-methyl acetamide, hydrochloride, mp. 121-124C.

Analysis: Calcd for C H ClNo C 57.04; H, 7.36; CI, 12 95; N, 5.15 Found: C 56.80; H, 7.11; CI, |2.52; N, 5.22

The ir spectrum (KBr) exhibits bands at 3.41, 3.54 p. (aliphatic CH); 4.35, 4.90, 5.15, and 5.67 p.( broad salt bands); 6.06 p. (amide carbonyl); 6.28 and 6.60 p (aromatic C=C); 6.94, 8.06, 8.61, 8.76, and 9.76 y. (aryl ether). The nmr spectrum (CDCl has peaks 8 2.47 (s, 3), 8 2.95 (1,2, J=7 Hz), 8 3.16 (s, 3), 8 3,81 (t, 2, J=7Hz), 8 3.89 (s, 6), and 8 6.80 (s, 3).

EXAMPLE 6 The procedure of Example 1 is repeated, substituting for the acetoxyacetyl chloride stoichiometrical amounts of correspondingly substituted acyl halides and the following phenethylamides are obtained:

EXAMPLE 7 The procedure of Example 3 is repeated substituting for N-( p-chlorophenethyl)-2-hydroxyacetamide, acetate, stoichiometrical amounts of appropriatelysubstituted 2-hydroxyacetamide, alkanoates, and the following phenethylamides are obtained:

In evaluating the instant compounds for pharmacological activity, they are tested in vivo by standard methods with the following results.

The compound is administered to three mice (CF-l 14 to 24 grams) at each of the following doses: 400, 127, and 12.7 mg./kg.

The animals are watched for signs of general stimulation, general depression and autonomic activity and the observations are evaluated by methods described in detail in Turner, Screening Methods in Pharmacology, Academic Press, New York, p. 1965), in the section titled A Test Group for Central Depressants.

N-( 3,4-dimethoxyphenethyl)-2-hydroxyacetamide, administered orally suspended at 1% in an aqueous vehicle with polyethylene oxide sorbitan mono-oleate (p.o.), caused decreased motor activity and decreased respiration at 127 mg./kg., and administered intraperitoneally (i.p.) it caused decreased motor activity at 40 mg./kg. and decreased respiration at 127 mg./kg.; N 3 ,4-dimethoxyphenethyl glyoxylamide diph enylacetal, administered i.p., caused decreased motor activity and decreased respiration at 127 mg./kg.; N-94- chlorophenethyl)-2-hydroxyacetamide, acetate, i.p. 0 and p.o., caused decreased motor activity and decreased respiration at 127 mg./kg.; N-(4- chlorophenethyl)-2-hydroxyacetamide, administered p.o., caused decreased motor activity at 40 mg./kg. and

decreased respiration at 127 mg./kg.; and N-(3,-4-

dimethoxyphenethyl)-N-methylacetamide hydrochloride, administered p.o., caused decreased motor activity at 12.7 mg./kg. and administered i.p.,

caused decreased motor activity at 40 mg./kg. and decreased respiration at 127 mg./kg. There were no deaths at be highest dose used, 400 mg./kg.

In a standard test for bronchodilator activity [modified from Siegmund et al., J. PharmacoL, 90, 254 (1947)]the ability of the compound to protect a guinea pig against the bronchoconstrictor effects of a histamine mist is determined. A 0.2 percent (base) histamine diphosphate solution is atomized and sprayed into a closed chamber for 60 seconds. The guinea pig is then placed into the chamber and observed for asphyxia] effects. When convulsions are imminent, the pig is removed from the chamber and allowed to recover. The time from placing the pig in the chamber until convulsions are imminent is recorded and is designated pre-convulsion time. Five pigs are used and control times are obtained for each pig in the morning. Only pigs having control times in the range of 50-100 seconds are used in the test. After a 3.5 to 4 hour recovery period the pigs are administered the drug intraperitoneally and 15 minutes later are again exposed to the histamine aerosol. An animal that can withstand three times its morning preconvulsion time is considered completely protected. Individual control (C) and post drug convulsion times (T) are recorded and an activity value calculated by the formula, (TIC). A mean (T/C) value greater than 1.5 indicates activity.

In this test, N-(3,4-dimethoxyphenethyl)-2-hydrox-,

yacetamide administered i.p. in saline had a T/C of 1.85 at 25 mg./kg. and 1.86 at mg./kg.; N-(4- chlorophenethyl)-2-hydroxyacetamide, administered i.p. in saline, had a T/C of 1.53 at 50 mg./kg.; and N- (3,4-dimethoxyphenethyl)-N-methylacetamide hydrochloride, administered i.p. in saline, had a T/C of 

2. A compound as defined in claim 1 in the form of a hydrochloric acid addition salt.
 3. N-(3,4-dimethoxyphenethyl)glyoxylamide, diphenylacetal. 